4171-13-5Relevant articles and documents
Evaluation of the antiallodynic, teratogenic and pharmacokinetic profile of stereoisomers of valnoctamide, an amide derivative of a chiral isomer of valproic acid
Kaufmann, Dan,Yagen, Boris,Minert, Anne,Wlodarczyk, Bogdan,Finnell, Richard H.,Schurig, Volker,Devor, Marshall,Bialer, Meir
experimental part, p. 1228 - 1236 (2011/12/02)
The purpose of this study was to evaluate the stereoselective pain relieving (antiallodynic) activity, antiallodynic-anticonvulsant correlation, teratogenicity and pharmacokinetic profile of two stereoisomers of valnoctamide (VCD), a CNS-active amide derivative of a chiral isomer of valproic acid (VPA). The individual stereoisomers (diastereomers), (2R,3S)-VCD and (2S,3S)-VCD were synthesized and their antiallodynic activity was evaluated in rats using the spinal nerve ligation model of neuropathic pain. The pharmacokinetic profile of the two stereoisomers was evaluated in rats following: 1) i.p. administration of racemic-VCD, 2) i.p. administration of the individual stereoisomers (2R,3S)-VCD and (2S,3S)-VCD. Teratogenicity of racemic-VCD and its two individual stereoisomers was evaluated in a SWV mouse strain known to be highly susceptible to VPA-induced teratogenicity. Racemic-VCD, (2R,3S)-VCD and (2S,3S)-VCD showed a dose-related reversal of tactile allodynia with ED50 values of 52, 61 and 39 mg/kg, respectively. (2S,3S)-VCD was significantly more potent than (2R,3S)-VCD but the opposite is true for its anticonvulsant-effect. In the teratogenicity evaluation racemic-VCD and its two individual stereoisomers showed mild embryotoxicity at doses 7-10 times higher than their antiallodynic-ED50 values, while (2S,3S)-VCD was significantly less embryotoxic than (2R,3S)-VCD and racemic-VCD. Following administration of the racemic-VCD there was an increase in the primary pharmacokinetic parameters of (2S,3S)-VCD but not of (2R,3S)-VCD. This study demonstrates that both racemic-VCD and its stereoisomers show high potency as antiallodynic compounds and possess a wide safety margin. (2S,3S)-VCD is more potent and less embryotoxic than (2R,3S)-VCD and thus, has a potential to become a candidate for development as a new drug for treating neuropathic pain.
Potent anticonvulsant urea derivatives of constitutional isomers of valproic acid
Shimshoni, Jakob Avi,Bialer, Meir,Wlodarczyk, Bogdan,Finnell, Richard H.,Yagen, Boris
, p. 6419 - 6427 (2008/03/30)
Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a mouse model for AED-induced teratogenicity. The urea derivatives of three VPA constitutional isomers propylisopropylacetylurea, diisopropylacetylurea, and 2-ethyl-3-methyl-pentanoylurea displayed a broad spectrum of anticonvulsant activity in rats with a clear superiority over their corresponding amides and acids. Enanatiomers of propylisopropylacetylurea and propylisopropylacetamide revealed enantioselective anticonvulsant activity, whereas only enantiomers of propylisopropylacetylurea displayed enantioselective teratogenicity. These potent urea derivatives caused neural tube defects, but only at doses markedly exceeding their effective dose, whereas VPA showed no separation between its anticonvulsant activity and teratogenicity. The broad spectrum of anticonvulsant activity of the urea derivatives coupled with their wide safety margin make them potential candidates to become new, potent AEDs.
